ABSTRACT
The aminocarbonylation of alkenes is a powerful method for accessing the ß-amino carbonyl motif that remains underdeveloped. Herein, the development of intermolecular aminocarbonylation reactivity of iminoisocyanates with alkenes is presented. This includes the discovery of a fluorenone-derived reagent, which was effective for many alkene classes and facilitated derivatization. Electron-rich substrates were most reactive, and this indicated that the LUMO of the iminoisocyanate is reacting with the HOMO of the alkene. Computational and experimental results support a concerted asynchronous [3 + 2] cycloaddition involving an iminoisocyanate, which was observed for the first time by FTIR under the reaction conditions. The products of this reaction are complex azomethine imines, which are precursors to valuable ß-amino carbonyl compounds such as ß-amino amides and esters, pyrazolones, and bicyclic pyrazolidinones. A kinetic resolution of the azomethine imines by enantioselective reduction (s = 13-43) allows access to enantioenriched products. Overall, this work provides a new tool to convert alkenes into ß-amino carbonyl compounds.
ABSTRACT
Antithyroid drugs are usually considered first-line therapy for management of pediatric Graves' disease because they avoid permanent hypothyroidism, provide a chance for remission, and are less invasive than the alternatives of thyroidectomy or radioactive iodine. Methimazole (MMI) is the only antithyroid drug recommended in pediatrics due to the risk of propylthiouracil-induced liver toxicity. Allergic reactions with MMI occur in up to 10% of patients and, when mild, can be managed with concurrent antihistamine therapy. Guidelines recommend discontinuation of MMI with serious allergic reactions. We present the case of an adolescent girl with Graves' disease and a serious allergic reaction after starting MMI whose family refused radioactive iodine and was reluctant to proceed to surgery. Antihistamine therapy was successfully used to allow continued treatment with MMI. This case demonstrates extension of management guidelines for minor cutaneous allergic reactions to MMI, through the use of antihistamines for a serious allergic reaction, allowing us to continue MMI and provide treatment consistent with the family's preferences and values.
Subject(s)
Antithyroid Agents/adverse effects , Antithyroid Agents/therapeutic use , Diphenhydramine/therapeutic use , Drug Hypersensitivity/diagnosis , Drug Hypersensitivity/drug therapy , Graves Disease/drug therapy , Histamine H1 Antagonists/therapeutic use , Methimazole/adverse effects , Methimazole/therapeutic use , Adolescent , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Humans , Treatment OutcomeABSTRACT
Complex cyclic azomethine imines possessing a ß-aminocarbonyl motif can be accessed readily from simple alkenes and hydrazones. This alkene aminocarbonylation approach allows formation of ketone-derived azomethine imines of unprecedented complexity. Since unsymmetrical hydrazones are used, two stereoisomers are formed: the reactivity of chiral derivatives is explored in both intra- and intermolecular systems.
Subject(s)
Alkenes/chemistry , Azo Compounds/chemical synthesis , Hydrazones/chemistry , Imines/chemical synthesis , Thiosemicarbazones/chemical synthesis , Azo Compounds/chemistry , Catalysis , Combinatorial Chemistry Techniques , Cyclization , Imines/chemistry , Ketones/chemical synthesis , Ketones/chemistry , Molecular Structure , Stereoisomerism , Thiosemicarbazones/chemistryABSTRACT
Cyclic azomethine imines possessing a ß-aminocarbonyl motif are accessed from simple alkene and hydrazone starting materials. A thermal, concerted alkene aminocarbonylation pathway involving an imino-isocyanate intermediate is proposed and supported by DFT calculations. A notable feature of the process is the steric shielding present in the dipoles formed, which allows for facile purification of the products by chromatography or crystallization. In addition, a fluorenone-derived reagent is reported, which provides reactivity with several alkene classes and allows for mild derivatization of the dipoles into ß-aminoamides, ß-aminoesters, and ß-amino acids.
Subject(s)
Alkenes/chemistry , Azo Compounds/chemistry , Imines/chemistry , Imines/chemical synthesis , Thiosemicarbazones/chemistry , Chemistry Techniques, Synthetic , Hydrazones/chemistry , Ketones/chemistryABSTRACT
The challenge of achieving selective and predictable functionalizations at C-H bonds with complex poly(hetero)aromatic substrates was addressed by two different approaches. Site-selectivity can be obtained by applying various reaction conditions that are (hetero)arene specific to substrates that contain indoles, pyridine N-oxide, and polyfluorinated benzenes. An experimental classification of electron-rich heteroarenes based on their reactivity toward palladium-catalyzed C-H functionalization was established, the result of which correlated well with the order of reactivity predicted by the DFT-calculated concerted metalation-deprotonation (CMD) pathway. Model substrates containing two reactive heteroarenes were then reacted under general reaction conditions to demonstrate the applicability this reactivity chart in predicting the regioselectivity of the palladium-catalyzed direct arylation and benzylation reactions.
